The present invention, in some embodiments thereof, relates to methods of treating autoimmune diseases of the central nervous system (CNS) and neurodegenerative diseases.
Multiple Sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) characterized by damage to the neuronal myelin sheath, which results in different levels of muscle paralysis that can lead to death. Epidemiological studies show a majority of patients with MS initially develop a relapsing-remitting form of the disease that can develop into secondary-progressive MS. Understanding the mechanisms leading to cumulative neurological disability in multiple sclerosis and further developing effective therapeutic strategies aiming at reduce disease progression is a major goal in MS research.
Innate immunity including dendritic cells, macrophages and activated microglia cells are the key effectors for tissue injury in inflammatory conditions of the CNS. Macrophages do not need activation signals from adaptive immunity to mediate demyelination and tissue injury in the brain. Furthermore, macrophage can promote inflammation through a variety of mechanisms, including the induction of pro-inflammatory cytokines, stimulation of monocyte recruitment and the inhibition of T-cell apoptosis in the lesions.
Since its discovery, Insulin-degrading enzyme (IDE) is considered as an important therapeutic target in diabetes reasoned that inhibitors of IDE would be an ideal anti-diabetic therapy, as they would slow the degradation of insulin.
IDE is an approximately 110 kDa thiol zinc-metalloendopeptidase located in cytosol, peroxisomes, endosomes, and on the cell surface. This enzyme cleaves small proteins of diverse sequences many of which share a propensity to form β-pleated sheet-rich amyloid fibrils, including amyloid β-protein (Aβ), insulin, glucagon, amylin, atrial natriuretic factor and calcitonin [Simkin et al. (1949) Arch Biochem 24: 422-428].
The IDE region of chromosome 10q has been genetically linked to type 2 diabetes mellitus [DM2, Ghosh et al. (2000) Am J Hum Genet. 67:1174-1185; Wiltshire et al. (2002) Am J Hum Genet. 70:543-546] and to elevated fasting glucose levels [Meigs et al. (2002) Diabetes 51:833-840]. Moreover, IDE−/− mice had hyperinsulinemia and glucose intolerance, hallmarks of DM2 [Farris et al. (2003) Proc Natl Acad Sci USA 100:4162-4167]. This model demonstrated that in vivo deficiency of a protease responsible for degrading insulin results in hyperglycemia in response to a glucose load (i.e., glucose intolerance).
Reports have further suggested the role of IDE in degradation of Aβ in Alzheimer's disease [Farris et al., supra]. The elevation of cerebral Aβ in IDE−/− model animals (approximately 10-65%) validated a role for IDE in Aβ proteolysis in vivo, however, there are most likely additional mechanisms of Aβ clearance in the intact brain, especially for Aβ42. Other proteases (e.g., NEP, endothelin-converting enzyme) may participate in Aβ clearance and partially compensate for the lack of IDE function.
IDE is also the cellular receptor mediating varicella-zoster virus (VZV) infection and cell-to-cell spreading [Li et al. (2006) Cell 127:305-316]. Down regulation of IDE by siRNA, or blocking IDE with an antibody, with a soluble IDE protein (extracted from the liver) or with a bacitracin inhibited VZV infection [Li et al., supra]. IDE interacts with glycoprotein E (gE), which is essential for virus infection, through the glycoprotein's extracellular domain, however, IDE does not degrade VZV.
The solved crystal structure of IDE [Shen et al. (2006) Nature 443:870-874] revealed that the amino- and carboxy-terminal domains of IDE (IDE-N and IDE-C, respectively) form a proteolytic chamber containing the zinc-binding active site, just large enough to encapsulate insulin. Extensive contacts between IDE-N and IDE-C keep the degradation chamber of IDE inaccessible to substrates. Repositioning of the IDE domains (shifting IDE-close to its active form IDE-open) enables substrate access to the catalytic cavity. The activity of IDE toward a vast array of physiological substrates can be partially explained by the detailed crystal structure of the enzyme. The structural data revealed that IDE is shaped like a clam shell, consisting of two bowl-shaped halves connected by a flexible hinge, which allows the enzyme to exist in two conformations, closed and open. During catalytic processing of substrates, the enzyme switches from the open structure to the closed configuration and back to the open structure as IDE binds, catalyzes, and then releases its substrate, respectively. The extended hydrogen bonding between the two halves of IDE creates a “latch” that acts to maintain the enzyme in the closed state. Mutations that promote the open conformation have been shown to improve the protease's efficiency in cleaving the substrate by as much as 30- to 40-fold [Shen et al., supra]. As it was suggested that the rate-limiting step may be the speed at which the enzyme can reopen and then clamp down on a new morsel rather than the time it takes to chew something up.
Alzheimer's disease (AD) is the most common type of dementia affecting more than 18 million people worldwide. The main role of beta amyloid (A13) peptide as a to mediator in AD is derived from the fact that it accumulates in the brain several decades before the disease is evident. The accumulation of extracellular and intracellular Aβ can adversely affect distinct molecular and cellular pathways, thereby facilitating tau phosphorylation, aggregation, and an accumulation of neurofibrillary tangle (NFT) formation. Aβ and NFT exhibit synergistic effects that finally lead to an acceleration of neurodegenerative mechanisms involved in metabolism, cellular detoxification, mitochondrial dysfunction, and energy deficiency which results in the formation of neuritic plaques. A number of studies suggest an association between Alzheimer's disease (AD) and diabetes: AD patients show impaired insulin function, which is associated with cognitive deficits. In fact is has been suggested that IDE dysfunction plays a role in Alzheimer's progression.
U.S. Patent Application 20090088367 teaches methods for the prevention or treatment of dementia and other neurological conditions by upregulating the activity of IDE such that insulin competes less efficiently with beta-amyloid protein for the IDE.
Additional Related Art: WO2010/086867